SENP1 and SENP2 regulate SUMOylation of amyloid precursor protein.
SENP1 and SENP2 regulate SUMOylation of amyloid precursor protein.
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DOI：
10.1016/j.heliyon.2018.e00601
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发表时间：
2018-04
期刊：
影响因子：
4
通讯作者：
Niikura T
中科院分区：
文献类型：
--
作者：
Maruyama T;Abe Y;Niikura T
β淀粉样蛋白（Amyloid β）是阿尔茨海默病（Alzheimer's disease，AD）发病机制中的关键分子，由淀粉样前体蛋白（amyloid precursor protein，APP）经分泌酶裂解而产生。APP在β-分泌酶的切割位点附近被SUMO化。APP的SUMO化可减少淀粉样β蛋白的产生，但其调控机制尚不清楚。SUMO化是靶蛋白的赖氨酸残基处的修饰，由活化、缀合和连接酶介导，并由sentrin/SUMO特异性蛋白酶（SENP）家族逆转。在此，我们发现SENP 1和SENP 2均诱导APP的去SUMO化。使用定量PCR，我们还发现SENP 1的表达仅在雌性小鼠中以年龄依赖性方式增加，而SENP 2的表达不增加。免疫印迹分析结果表明，蛋白表达与PCR结果一致。与男性相比，女性在人类中具有更高的AD发病率，并且在AD小鼠模型中显示出更具侵袭性的淀粉样蛋白病理学。我们的研究结果为了解SUMO化在AD发病机制性别差异中的作用提供了线索。
Amyloid β, a key molecule in the pathogenesis of Alzheimer's disease (AD), is produced from amyloid precursor protein (APP) by the cleavage of secretases. APP is SUMOylated near the cleavage site of β-secretase. SUMOylation of APP reduces amyloid β production, but its regulatory system is still unclear. SUMOylation, a modification at a lysine residue of a target protein, is mediated by activating, conjugating, and ligating enzymes and is reversed by a family of sentrin/SUMO-specific proteases (SENPs). Here, we found that both SENP1 and SENP2 induced de-SUMOylation of APP. Using quantitative PCR, we also found that expression of SENP1 but not SENP2 increased in an age-dependent manner only in female mice. The results of immunoblot analyses showed that the protein expression was consistent with the PCR results. Females, compared to males, have a higher incidence of AD in humans and show more aggressive amyloid pathology in AD mouse models. Our results provide a clue to understanding the role of SUMOylation in the sex difference in AD pathogenesis.